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Collection Highlights

Diagnostic Molecular Pathology A Guide to Applied

Molecular Testing 1st Edition William B. Coleman

Cellular and Molecular Basis of Mitochondrial Inheritance

Mitochondrial Disease and Fitness Peter Sutovsky

Rosenberg’s Molecular and Genetic Basis of Neurological

and Psychiatric Disease Roger N. Rosenberg

Molecular Biology of Placental Development and Disease

William R. Huckle (Eds.)
The molecular basis of drug addiction 1st Edition Rahman

Molecular Basis of Oxidative Stress Chemistry Mechanisms

and Disease Pathogenesis 1st Edition Frederick A.
Villamena

Rosenberg's Molecular and Genetic Basis of Neurological

and Psychiatric Disease 6th Edition Roger N. Rosenberg

Pathology of Heart Disease in the Fetus Infant and Child

Autopsy Surgical and Molecular Pathology 1st Edition
Michael T. Ashworth

Molecular Basis of Nutrition and Aging: A Volume in the

Molecular Nutrition Series 1st Edition Marco Malavolta Phd
Molecular Pathology
The Molecular Basis of Human
Disease

SECOND EDITION

Editors

William B. Coleman

Gregory J. Tsongalis

2
Table of Contents
Cover image

Title page

Copyright

Dedication

List of Contributors

Preface

Acknowledgments

Chapter 1. Molecular Mechanisms of Cell Death

Introduction

Modes of Cell Death

Structural Features of Necrosis and Apoptosis

Cellular and Molecular Mechanisms Underlying Necrotic Cell Death

Pathways to Apoptosis

Mitochondria

Nucleus

Endoplasmic Reticulum

Lysosomes

Shared Pathways to Necrosis and Apoptosis

Programmed Necrosis

3
 Concluding Remark

Chapter 2. Acute and Chronic Inflammation Induces Disease Pathogenesis

Introduction

Leukocyte Adhesion, Migration, and Activation

Acute Inflammation and Disease Pathogenesis

Pattern Recognition Receptors and Inflammatory Responses

Chronic Inflammation and Acquired Immune Responses

Tissue Remodeling During Acute and Chronic Inflammatory Disease

Chapter 3. Infection and Host Response

Introduction

Microbes and Hosts—Balance of Power?

The Structure of the Immune Response

Regulation of Immunity

Pathogen Strategies

Staphylococcus aureus: The Extracellular Battleground

Mycobacterium tuberculosis and the Macrophage

Herpes Simplex Virus: Taking Over

The African Trypanosome and Antibody Diversity: Dueling Genomes

HIV: The Immune Guerilla

Perspectives

Chapter 4. Neoplasia
Introduction

Cancer Statistics and Epidemiology

Classification of Neoplastic Diseases

Characteristics of Benign and Malignant Neoplasms

Clinical Aspects of Neoplasia

Chapter 5. Basic Concepts in Human Molecular Genetics

Introduction

4
 Molecular Structure of DNA, DNA Transcription, and Protein Translation

Molecular Pathology and DNA Repair Mechanisms

Modes of Inheritance

Central Dogma and Rationale for Genetic Testing

Allelic Heterogeneity and Choice of Analytical Methodology

Conclusion

Chapter 6. The Human Genome: Understanding Human Disease in the Post-

Genomic Era
Introduction

Structure and Organization of the Human Genome

Overview of the Human Genome Project

Impact of the Human Genome Project on the Identification of Disease-Related Genes

Sources of Variation in the Human Genome

Types of Genetic Diseases

Genetic Diseases and Cancer

Perspectives

Chapter 7. The Human Transcriptome: Implications for Understanding, Diagnosing,

and Treating Human Disease
Introduction

Gene Expression Profiling—Early Attempts to Search for Candidate Genes Involved in

Normal Physiological Processes and Pathogenesis

Preparation of Target RNA From Biological and Clinical Specimens

Transcriptome Analysis Based on Microarrays—Technical Aspects

Transcriptome Analysis Based on RNA Sequencing—Technical Aspects

Bioinformatics I—Basic Processing of Microarray and RNA-seq Data

Bioinformatics II—Exploration and Statistical Evaluation of Transcriptomics Data

Repositories for Transcriptome Data

Trancriptome Analysis—Applications in Basic Research and Translational Medicine

Perspectives

5
Chapter 8. The Human Epigenome—Implications for the Understanding of Human
Disease
Introduction

Epigenetic Regulation of the Genome

Genomic Imprinting

Cancer Epigenetics

Human Disorders Associated With Epigenetics

Environment and the Epigenome

Chapter 9. Clinical Proteomics and Molecular Pathology

Understanding Cancer at the Molecular Level: An Evolving Frontier

Microdissection Technology Brings Molecular Analysis to the Tissue Level

Serum Proteomics: An Emerging Landscape for Early-Stage Cancer Detection

Chapter 10. Integrative Systems Biology

Introduction

Data Generation

Data Integration

Modeling Systems

Implications for Understanding Disease

Discussion

Chapter 11. Pathology: The Clinical Description of Human Disease

Introduction

Terms, Definitions, and Concepts

A Brief History of Approaches to Disease

Current Practice of Pathology

The Future of Diagnostic Pathology

Conclusion

Chapter 12. Understanding Molecular Pathogenesis: The Biological Basis of Human

Disease and Implications for Improved Treatment of Human Disease

6
 Introduction

Hepatitis C Virus Infection

Summary

Acute Myeloid Leukemia

Summary

Cystic Fibrosis

Summary

Chapter 13. Integration of Molecular and Cellular Pathogenesis: A Bioinformatics

Approach
Introduction

Overview of Bioinformatics

Database Resources

Data Analysis

The Future of Bioinformatics

Chapter 14. Molecular Basis of Cardiovascular Disease

Introduction

General Molecular Principles of Cardiovascular Diseases

The Cells of Cardiovascular Organs

Atherosclerosis

Ischemic Heart Disease

Aneurysms

Vasculitis

Valvular Heart Disease

Cardiomyopathies

Lymphatic Circulation

Chapter 15. Molecular Basis of Hemostatic and Thrombotic Diseases

Introduction and Overview of Coagulation

Disorders of Soluble Clotting Factors

Disorders of Fibrinolysis

7
 Disorders of Platelet Number or Function

The Thrombophilias

Chapter 16. Molecular Basis of Lymphoid and Myeloid Diseases

Introduction

Development of the Blood and Lymphoid Organs

Myeloid Disorders

Lymphocyte Disorders

Outlook for the Treatment of Leukemia

Chapter 17. Molecular Basis of Diseases of Immunity

Introduction

The Normal Immune System

Major Syndromes

The Hygiene Hypothesis

Chapter 18. Molecular Basis of Pulmonary Disease

Introduction

Neoplastic Lung and Pleural Diseases

Nonneoplastic Lung Disease

Interstitial Lung Diseases

Surfactant Dysfunction Diseases

Pulmonary Vascular Diseases

Chapter 19. Molecular Basis of Diseases of the Gastrointestinal Tract

Introduction

Gastric Cancer

Colorectal Cancer

Chapter 20. Molecular Basis of Liver Disease

Molecular Basis of Liver Development

Molecular Basis of Metabolic Zonation in the Liver

8
 Molecular Basis of Liver Regeneration

Liver Stem Cells in Liver Health and Disease

Molecular Basis of Hepatocyte Death

Molecular Basis of Nonalcoholic Fatty Liver Disease

Molecular Basis of Alcoholic Liver Disease

Molecular Basis of Hepatic Fibrosis and Cirrhosis

Molecular Basis of Hepatic Tumors

Chapter 21. Molecular Basis of Diseases of the Exocrine Pancreas

Introduction

Acute Pancreatitis

Inflammation: Cause and Consequence of Acinar Cell Damage

Chronic and Hereditary Pancreatitis

Summary

Chapter 22. Molecular Basis of Diseases of the Endocrine System

Introduction

The Pituitary Gland

The Thyroid Gland

The Parathyroid Gland

The Adrenal Gland

Puberty

Chapter 23. Molecular Basis of Gynecologic Diseases

Introduction

Benign and Malignant Tumors of the Female Reproductive Tract

Disorders Related to Pregnancy

Chapter 24. Molecular Basis of Kidney Disease

Introduction

Clinical Manifestations

Diagnosis of Renal Disease

9
 Specific Glomerular and Tubular Diseases

Tubulointerstitial Fibrosis

Conclusions

Chapter 25. Molecular Pathogenesis of Prostate Cancer

Introduction

Incidence and Etiology of Prostate Cancer

Genetic Contributions to Prostate Cancer Risk

Somatic Alterations in Gene Expression

Epigenetics

Advances in Mouse Models of Prostate Cancer

Conclusion

Chapter 26. Molecular Biology of Breast Cancer

Introduction

Histopathological Classification

Biomarkers

Gene Expression Profiling

Massively Parallel Sequencing

Conclusions

Chapter 27. Molecular Basis of Skin Disease

Introduction

Skin Diseases and Their Impact

Molecular Basis of Healthy Skin

Skin Development and Maintenance Provide New Insight Into the Molecular Mechanisms
of Disease

Molecular Pathology of Mendelian Genetic Skin Disorders

Molecular Pathology of Common Inflammatory Skin Diseases

Skin Proteins as Targets for Inherited and Acquired Disorders

Molecular Pathology of Skin Cancer

Molecular Diagnosis of Skin Disease

10
 New Molecular Mechanisms and Novel Therapies

Chapter 28. Molecular Basis of Bone Diseases

Introduction

Molecular Basis of Bone Modeling and Remodeling

Molecular Basis of Bone Disease Associated With Bone Matrix

Molecular Basis of Bone Disease Associated With Bone Resorption

Molecular Basis of Metabolic Bone Disease

Molecular Basis of Bone Infection and Inflammation

Molecular Basis of Bone Cancer

Molecular Basis of Bone Metastasis

Chapter 29. Molecular Basis of Diseases of the Nervous System

Anatomy of the Central Nervous System

Neurodevelopmental Disorders

Neurological Injury: Stroke, Neurodegeneration, and Toxicants

Neoplasia

Disorders of Myelin

Chapter 30. Molecular Diagnosis of Human Disease

Introduction

Regulatory Agencies and CLIA

Quality Assurance, Quality Control, and External Proficiency Testing

Method Validation

Clinical Utility

Molecular Laboratory Subspecialties

Chapter 31. Molecular Assessment of Human Diseases in the Clinical Laboratory

Introduction

Molecular Pathology Techniques

Clinical Applications

Emerging Technologies

11
Chapter 32. Pharmacogenomics and Personalized Medicine in the Treatment of
Human Diseases
Introduction

Historical Perspective

Genotyping Technologies

PGx and Drug Metabolism

Drug–Drug Interactions

PGx and Drug Triansporters

PGx and Drug Targets

PGx Applied to Oncology

Targeted Therapies in Oncology

Challenges Encountered

Conclusion

Index

12
Copyright
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This book and the individual contributions contained in it are protected under
copyright by the Publisher (other than as may be noted herein).

Notices
Knowledge and best practice in this field are constantly changing. As new research
and experience broaden our understanding, changes in research methods,
professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and
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they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors,
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13
A catalog record for this book is available from the Library of Congress

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14
Dedication

The wealth of information contained in this textbook represents the

culmination of innumerable small successes that emerged from the
ceaseless pursuit of new knowledge by countless experimental
pathologists working around the world on all aspects of human disease.
Their ingenuity and hard work have dramatically advanced the field of
molecular pathology over time and in particular in the last three decades.
This book is a tribute to the dedication, diligence, and perseverance of the
individuals who have contributed to the advancement of our
understanding of the molecular basis of human disease, especially the
graduate students, laboratory technicians, and postdoctoral fellows,
whose efforts are so frequently taken for granted, whose
accomplishments are so often unrecognized, and whose contributions are
so quickly forgotten.

The second edition of Molecular Pathology: The Molecular Basis of Human

Disease is dedicated to the memory of Oliver Smithies, DPhil,
Weatherspoon Eminent Distinguished Professor of Pathology and
Laboratory Medicine at the University of North Carolina School of
Medicine (Chapel Hill, NC) who passed away on January 10, 2017 at the
age of 91 years. Dr. Smithies was a cherished colleague to everyone at
UNC and renowned for his gentle character, generous spirit, infectious
curiosity, and passion for science. He was a friend to all and eager to help
others succeed. Dr. Smithies was also a giant in the field of genetics who
made numerous seminal discoveries over the course of his lifelong career
(over 70 years at the bench). In 2007, he was a corecipient of the Nobel
Prize for Physiology or Medicine for his contributions to the development
of techniques for homologous recombination, which enable genetic
modification of mammalian cells. These techniques provide the
methodological foundation for engineered (transgenic and knockout)
animal models of disease, which have been so valuable in the study of
human diseases. Despite his tremendous accomplishments, status in the

15
 field, and numerous awards and honors, Dr. Smithies was unpretentious
and approachable. We are proud to have known him for many years and
for the example he provided for us and so many others as a distinguished
and accomplished experimental pathologist and a genuinely good
person. Even though he is gone, Dr. Smithies continues to inspire
generations of scientists who were fortunate enough to have known him
to do their best work.

We also dedicate the second edition of Molecular Pathology: The Molecular

Basis of Human Disease to the many people who have played crucial roles
in our successes. We thank our many scientific colleagues, past and
present, for their camaraderie, collegiality, and support. We especially
thank our scientific mentors for their example of research excellence. We
are truly thankful for the positive working relationships and friendships
that we have with our faculty colleagues. We also thank our students for
teaching us more than we may have taught them. We thank our parents
for believing in higher education, for encouragement through the years,
and for helping our dreams into reality. We thank our brothers and
sisters, and extended families, for the many years of love, friendship, and
tolerance. We thank our wives, Monty and Nancy, for their unqualified
love, unselfish support of our endeavors, understanding of our work
ethic, and appreciation for what we do. Lastly, we give a special thanks to
our children, Tess, Sophie, Pete, and Zoe. Their achievements and
successes as young adults are a greater source of pride for us than our
own accomplishments. As when they were children, we thank them for
providing an unwavering bright spot in our lives, for their unbridled
enthusiasm and boundless energy, and for giving us a million reasons to
take an occasional day off from work just to have fun. Now that they are
older, we cherish their friendship and value their companionship.
William B. Coleman

Gregory J. Tsongalis

16
List of Contributors
Philippe Aftimos, MD, Institut Jules Bordet, Université Libre de Bruxelles,
Brussels, Belgium

Hatem A. Azim Jr. MD, PhD, Institut Jules Bordet, Université Libre de Bruxelles,
Brussels, Belgium

Sheldon I. Bastacky, MD, Department of Pathology, University of Pittsburgh

School of Medicine, Pittsburgh, PA, United States

David O. Beenhouwer, MD
Department of Medicine, David Geffen School of Medicine at University of
California, Los Angeles, CA, United States
Division of Infectious Diseases, Veterans Affairs Greater Los Angeles Healthcare
System, Los Angeles, CA, United States

Jaideep Behari, MD, PhD, Department of Medicine, Division of Gastroenterology,

Hepatology, and Nutrition, University of Pittsburgh, School of Medicine, Pittsburgh,
PA, United States

Joseph R. Biggs, PhD, Department of Pathology and Division of Biological

Sciences, University of California San Diego, La Jolla, CA, United States

Sheldon Campbell, MD, PhD, Department of Laboratory Medicine, Yale School

of Medicine, VA Connecticut Healthcare System, New Haven, CT, United States

Wai-Yee Chan, PhD, School of Biomedical Sciences, Faculty of Medicine, Lo

Kwee-Seong Integrated Biomedical Sciences Building, The Chinese University of
Hong Kong, Shatin, Hong Kong SAR

William B. Coleman, PhD, Department of Pathology and Laboratory Medicine,

Curriculum in Toxicology, UNC Program in Translational Medicine, UNC
Lineberger Comprehensive Cancer Center, University of North Carolina School of
Medicine, Chapel Hill, NC, United States

Massimiliano M. Corsi Romanelli, MD, PhD

Department of Biomedical Sciences for Health, Università degli Studi di Milano,
Milan, Italy
U.O.C SMEL-1 Patologia Clinica IRCCS Policlinico San Donato, Milan, Italy

17
Robin D. Couch, PhD, Department of Chemistry and Biochemistry, George
Mason University, Manassas, VA, United States

Justin B. Davis, PhD, Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, United States

Sophie J. Deharvengt, PhD, Laboratory for Clinical Genomics and Advanced

Technology (CGAT), Department of Pathology and Laboratory Medicine,
Dartmouth Hitchcock Medical Center, Lebanon, NH, United States

Armando J. Del Portillo, MD, PhD, Department of Pathology and Cell Biology,
Columbia University College of Physicians and Surgeons, New York, NY, United
States

Virginia Espina, PhD, MT(ASCP), Center for Applied Proteomics and Molecular
Medicine, George Mason University, Manassas, VA, United States

Manel Esteller, MD, PhD

Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research
Institute (IDIBELL), Barcelona, Catalonia, Spain
Physiological Sciences Department, School of Medicine and Health Sciences,
University of Barcelona (UB), L’Hospitalet, Catalonia, Spain
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia,
Spain

Carol F. Farver, MD, Director, Pulmonary Pathology, Vice Chair for Education,
Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH,
United States

Michael D. Feldman, MD, Professor of Pathology, The Perelman School of

Medicine, University of Pennsylvania, Philadelphia, PA, United States

Susan L. Fink, MD, PhD, University of Washington, Seattle, WA, United States

Margaret Flanagan, MD, Department of Pathology, Stanford University, Palo

Alto, CA, United States

Claudia Fredolini, PhD, SciLifeLab, School of Biotechnology, KTH – Royal

Institute of Technology, Solna, Sweden

William K. Funkhouser Jr. MD, PhD, Department of Pathology and Lab

Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United
States

Matthias E. Futschik, PhD, School of Biomedical & Healthcare Sciences, Plymouth

University Peninsula Schools of Medicine and Dentistry, Plymouth, United
Kingdom

Emanuela Galliera, PhD

Department of Biomedical, Surgical and Oral Sciences, Università degli Studi di

18
Milano, Milan, Italy
IRCCS Galeazzi Orthopedic Institute, Milan, Italy

Avrum I. Gotlieb, MDCM, FRCPC, Department of Laboratory Medicine and

Pathobiology, Faculty of Medicine, University of Toronto, Laboratory Medicine
Program, University Health Network, Toronto, ON, Canada

Robert F. Hevner, MD, PhD, Department of Neurological Surgery, Seattle

Children’s Hospital Research Institute, Seattle, WA, United States

W. Edward Highsmith Jr. PhD, Department of Laboratory Medicine and

Pathology, Mayo Clinic, Rochester, MN, United States

Christopher Dirk Keene, MD, PhD, Department of Pathology, University of

Washington, Seattle, WA, United States

Nigel S. Key, MD, Department of Medicine, Division of Hematology/Oncology,

University of North Carolina, Chapel Hill, NC, United States

Christine M. Koellner, MS, CGC, Department of Laboratory Medicine and

Pathology, Mayo Clinic, Rochester, MN, United States

John J. Lemasters, MD, PhD, Departments of Drug Discovery & Pharmaceutical

Sciences and Biochemistry & Molecular Biology, Medical University of South
Carolina, Charleston, SC, United States

Markus M. Lerch, MD, Department of Internal Medicine A, Ernst-Moritz-Arndt-

Universität Greifswald, Greifswald, Germany

Lance A. Liotta, PhD, Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, United States

Youhua Liu, PhD, Department of Pathology, University of Pittsburgh School of

Medicine, Pittsburgh, PA, United States

Karen H. Lu, MD, Department of Gynecologic Oncology, University of Texas

M.D. Anderson Cancer Center, Houston, TX, United States

Nicholas W. Lukacs, PhD, Department of Pathology, University of Michigan

Medical School, Ann Arbor, MI, United States

Alice D. Ma, MD, Department of Medicine, Division of Hematology/Oncology,

University of North Carolina, Chapel Hill, NC, United States

Karlyn Martin, MD, Department of Medicine, Division of Hematology/Oncology,

University of North Carolina, Chapel Hill, NC, United States

Julia Mayerle, MD, Department of Internal Medicine A, Ernst-Moritz-Arndt-

Universität Greifswald, Greifswald, Germany

Kara A. Mensink, MS, CGC, Department of Laboratory Medicine and Pathology,

19
Mayo Clinic, Rochester, MN, United States

Samuel C. Mok, PhD, Department of Gynecologic Oncology, University of Texas

M.D. Anderson Cancer Center, Houston, TX, United States

Satdarshan P.S. Monga, MD, Division of Experimental Pathology, Department of

Pathology, Division of Gastroenterology, Hepatology and Nutrition, Department of
Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, School of
Medicine, Pittsburgh, PA, United States

Thomas J. Montine, MD, PhD, Department of Pathology, Stanford University,

Palo Alto, CA, United States

Jason H. Moore, PhD, Division of Informatics, Department of Biostatistics and

Epidemiology, Institute for Biomedical Informatics, The Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA, United States

Markus Morkel, PhD, Laboratory of Molecular Tumor Pathology and Tumor

Systems Biology, Charité – Universitätsmedizin Berlin, Berlin, Germany

Karl Munger, PhD, Department of Developmental, Molecular and Chemical

Biology, Tufts University School of Medicine, Boston, MA, United States

Zoltan Nagymanyoki, MD, PhD, Department of Pathology, West Pacific Medical

Laboratory, Santa Fe Springs, CA, United States

Robert D. Nerenz, PhD, Assistant Professor of Pathology and Laboratory

Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States

Alan L.-Y. Pang, PhD, TGD Life Company Limited, Hong Kong Science Park,
Shatin, Hong Kong SAR

Emanuel Petricoin, PhD, Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, United States

Catherine Ptaschinski, PhD, Department of Pathology, University of Michigan

Medical School, Ann Arbor, MI, United States

Reinhold Schäfer, PhD

Charité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Berlin,
Germany
German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg,
Germany

Matthias Sendler, MD, Department of Internal Medicine A, Ernst-Moritz-Arndt-

Universität Greifswald, Greifswald, Germany

Antonia R. Sepulveda, MD, PhD, Department of Pathology and Cell Biology,

Columbia University College of Physicians and Surgeons, New York, NY, United
States

20
Christine Sers, PhD, Laboratory of Molecular Tumor Pathology and Tumor
Systems Biology, Charité – Universitätsmedizin Berlin, Berlin, Germany

Lawrence M. Silverman, PhD, Department of Pathology, University of Virginia

Health System, Charlottesville, VA, United States

Joshua A. Sonnen, MD, Department of Pathology, University of Utah, Salt Lake

City, UT, United States

Christos Sotiriou, MD, PhD, Institut Jules Bordet, Université Libre de Bruxelles,
Brussels, Belgium

Roderick J. Tan, MD, PhD, Renal-Electrolyte Division, Department of Medicine,

University of Pittsburgh School of Medicine, Pittsburgh, PA, United States

Gregory J. Tsongalis, PhD

The Audrey and Theodor Geisel School of Medicine at Dartmouth, Hanover, NH,
United States
Laboratory for Clinical Genomics and Advanced Technology (CGAT), Department
of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center,
Lebanon, NH, United States

Vesarat Wessagowit, MD, PhD, The Institute of Dermatology, Rajvithi Phyathai,

Bangkok, Thailand

Eli S. Williams, PhD, Department of Pathology, University of Virginia Health

System, Charlottesville, VA, United States

Kwong-Kwok Wong, PhD, Department of Gynecologic Oncology, University of

Texas M.D. Anderson Cancer Center, Houston, TX, United States

Dani S. Zander, MD, Department of Pathology and Laboratory Medicine,

University of Cincinnati, Cincinnati, OH, United States

Dong-Er Zhang, PhD, Department of Pathology and Division of Biological

Sciences, University of California San Diego, La Jolla, CA, United States

Weidong Zhou, MD, PhD, Center for Applied Proteomics and Molecular
Medicine, George Mason University, Manassas, VA, United States

21
Preface
Pathology is the study of disease. The field of pathology emerged from the
application of the scientific method to the study of human disease. Thus, pathology
as a discipline represents the complementary intersection of medicine and basic
science. Early pathologists were typically practicing physicians who described the
various diseases that they treated and made observations related to factors that
contributed to the development of these diseases. The description of disease evolved
over time from gross observation to microscopic inspection of diseased tissues based
on the light microscope and more recently to the ultrastructural analysis of disease
with the advent of the electron microscope. As hospital-based and community-based
registries of disease emerged, the ability of investigators to identify factors that cause
disease and assign risk to specific types of exposures expanded to increase our
knowledge of the epidemiology of disease. Although descriptive pathology can be
dated to the earliest written histories of medicine and the modern practice of
diagnostic pathology dates back perhaps 200 years, the elucidation of mechanisms of
disease and linkage of disease pathogenesis to specific causative factors emerged
more recently from studies in experimental pathology. The field of experimental
pathology embodies the conceptual foundation of early pathology—the application
of the scientific method to the study of disease—and applies modern investigational
tools of cell and molecular biology to advanced animal model systems and studies of
human subjects. The molecular era of biological science began over 60 years ago,
whereas recent advances in our knowledge of molecular mechanisms of disease have
propelled the field of molecular pathology. These advances were facilitated by
significant improvements and new developments associated with the techniques and
methodologies available to pose questions related to the molecular biology of normal
and diseased states affecting cells, tissues, and organisms. Today, molecular
pathology encompasses the investigation of the molecular mechanisms of disease
and interfaces with translational medicine where new basic science discoveries form
the basis for the development of new strategies for disease prevention, new
therapeutic approaches and targeted therapies for the treatment of disease, and new
diagnostic tools for disease diagnosis and prognostication.
With the remarkable pace of scientific discovery in the field of molecular
pathology, basic scientists, clinical scientists, and physicians have a need for a source
of information on the current state of the art of our understanding of the molecular
basis of human disease. More importantly, the complete and effective training of
today’s graduate students, medical students, postdoctoral fellows, and others, for
careers related to the investigation and treatment of human disease, requires
textbooks that have been designed to reflect our current knowledge of the molecular

22
mechanisms of disease pathogenesis, as well as emerging concepts related to
translational medicine. Most pathology textbooks provide information related to
diseases and disease processes from the perspective of description (what does it look
like and what are its characteristics), risk factors, disease-causing agents, and to
some extent, cellular mechanisms. However, most of these textbooks lack in-depth
coverage of the molecular mechanisms of disease. The reason for this is primarily
historical—most major forms of disease have been known for a long time, but the
molecular basis of these diseases is not always known or has been elucidated only
very recently. However, with rapid progress over time and improved understanding
of the molecular basis of human disease, the need emerged for new textbooks on the
topic of molecular pathology, where molecular mechanisms represent the focus.
In this second edition of Molecular Pathology: The Molecular Basis of Human Disease,
we have assembled a group of experts to discuss the molecular basis and
mechanisms of major human diseases and disease processes, presented in the
context of traditional pathology, with implications for translational molecular
medicine. This volume is intended to serve as a multiuse textbook that would be
appropriate as a classroom teaching tool for medical students, biomedical graduate
students, allied health students, and others (such as advanced undergraduates).
Furthermore, this textbook will be valuable for pathology residents and other
postdoctoral fellows who desire to advance their understanding of molecular
mechanisms of disease beyond what they learned in medical/graduate school. In
addition, this textbook is useful as a reference book for practicing basic scientists and
physician scientists who perform disease-related basic science and translational
research, who require a ready information resource on the molecular basis of various
human diseases and disease states. To be sure, our understanding of the many
causes and molecular mechanisms that govern the development of human diseases
is far from complete. Nevertheless, the amount of information related to these
molecular mechanisms has increased tremendously in recent years, and areas of
thematic and conceptual consensus have emerged. We have made an effort to
integrate accepted principles with broader theoretical concepts in an attempt to
present a current and comprehensive view of the molecular basis of human disease.
We hope that this second edition of Molecular Pathology: The Molecular Basis of Human
Disease will accomplish its purpose of providing students and researchers with in-
depth coverage of the molecular basis of major human diseases in the context of
traditional pathology so as to stimulate new research aimed at furthering our
understanding of these molecular mechanisms of human disease and advancing the
theory and practice of molecular medicine.
William B. Coleman
Gregory J. Tsongalis

23
Acknowledgments
The editors would like to acknowledge the significant contributions of a number of
people to the successful production of the second edition of Molecular Pathology: The
Molecular Basis of Human Disease.
We would like to thank the individuals who contributed to the content of this
volume. The remarkable coverage of the state of the art in the molecular pathology
of human disease would not have been possible without the hard work and diligent
efforts of the 62 authors of the individual chapters. Many of these contributors are
our long-time colleagues, collaborators, and friends, and they have contributed to
other projects that we have directed, and we sincerely appreciate their willingness to
contribute once again to a project that we found worthy. We especially thank the
contributors to this volume who were willing to work with us for the first time. This
group also includes some of our long-time friends and colleagues, as well as some
new friends. We look forward to working with all of these authors again in the
future. Each of these contributors provided us with an excellent treatment of their
topic, and we hope that they will be proud of their individual contributions to the
textbook. Furthermore, we would like to give a special thanks to our colleagues who
coauthored chapters with us for this textbook. There is no substitute for an excellent
coauthor when you are juggling the several responsibilities of concurrently editing
and contributing to a textbook. Collectively, we can all be proud of this volume, as it
is proof that the whole can be greater than the sum of its parts.
Thanks to Ms. Mara Conner (Senior Acquisitions Editor, Academic Press—Elsevier)
who worked with us on the first edition of this textbook. She embraced the concept
of this textbook when our ideas were not yet fully developed and encouraged us to
pursue the project. She was receptive to the model for this textbook that we
envisioned and worked closely with us to evolve the project into its final form.
Without Mara’s early support, the first edition of this textbook would not have been
so successful and this second edition would not have been possible.
We would also like to thank the many people who work for Academic Press
—Elsevier that made this project possible. We have not met and do not know many
of these people, but we appreciate their efforts to bring this textbook to its completed
form. Special thanks goes to three key people who made significant contributions to
this project on the publishing side and proved to be exceptionally competent and
capable. Ms. Tari Broderick (Senior Acquisitions Editor, Academic Press—Elsevier)
provided excellent oversight (and optimistic patience) during the construction and
editing of this edition of the textbook and has become our valued colleague as we
develop new projects. Ms. Lisa Eppich (Editorial Project Manager, Elsevier) provided

24
excellent support to us throughout this project. As we interacted with our
contributing authors, collected and edited manuscripts, and began production of the
textbook, Lisa assisted us greatly by being a constant reminder of deadlines, helping
us with communication with the contributors, and generally providing support for
details small and large, all of which proved to be critical. Ms. Anusha
Sambamoorthy (Project Manager, Elsevier) worked with us closely to ensure the
integrity of the content of the textbook as it moved from the edited manuscripts into
their final form. We thank her for her direct involvement with the production and
also for directing her excellent production team. It was a pleasure to work with Tari,
Lisa, and Anusha on this project. We hope that they enjoyed it as much as we did,
and we look forward to working with them again soon.
William B. Coleman
Gregory J. Tsongalis

25
CHAPTER 1

Molecular Mechanisms of
Cell Death
John J. Lemasters, MD, PhD Departments of Drug Discovery & Pharmaceutical Sciences and Biochemistry & Molecular
Biology, Medical University of South Carolina, Charleston, SC, United States

Abstract
Cell death is a fundamental pathophysiological process and also an essential event in
normal life and development. Although many stimuli cause death of cells, the mode of
cell death typically follows one of two patterns. The first is necrosis, or oncosis. Oncotic
necrosis is most often the result of profound metabolic disruption and is characterized by
cellular swelling leading to plasma membrane rupture with release of intracellular
contents. The second pattern is apoptosis, a form of programmed cell death. Apoptosis
causes the orderly resorption of individual cells initiated by well-defined pathways
involving activation of proteases called caspases. In contrast to necrotic cell death, which
typically occurs from adenosine triphosphate (ATP) depletion, apoptosis is an ATP-
requiring process. Several distinct organelles (plasma membrane, mitochondrion,
nucleus, endoplasmic reticulum, lysosome) give rise to signals that induce cell death. In
particular, mitochondrial permeabilization and dysfunction typically develop in both
necrosis and apoptosis. In some instances, apoptosis and necrosis share signaling
pathways, as occurs in programmed necrosis called necroptosis. In this way, apoptosis
and necrosis can represent extreme endpoints on a phenotypic continuum of lost cell
viability.

Keywords
Apoptosis; Caspase; Death receptor; DISC; Mitochondrial permeability transition; Necroptosis; Necrosis;
PARP; Reperfusion injury

OUTLINE
Introduction
Modes of Cell Death
Structural Features of Necrosis and Apoptosis
Oncotic Necrosis
Apoptosis

26
Cellular and Molecular Mechanisms Underlying Necrotic Cell Death
Metastable State Preceding Necrotic Cell Death
Mitochondrial Dysfunction and ATP Depletion
Mitochondrial Uncoupling in Necrotic Cell Killing
Mitochondrial Permeability Transition
Inner Membrane Permeability
Mitochondrial Permeability Transition Pore
pH-dependent Ischemia/Reperfusion Injury
Role of the Mitochondrial Permeability Transition in pH-Dependent
Reperfusion Injury
Oxidative Stress
Protein Kinase Signaling and the MPT
Other Stress Mechanisms Inducing Necrotic Cell Death
Poly (ADP-Ribose) Polymerase
Plasma Membrane Injury
Pathways to Apoptosis
Roles of Apoptosis in Biology
Plasma Membrane
Mitochondria
Cytochrome c Release
Regulation of the Mitochondrial Pathway to Apoptosis
Antiapoptotic Survival Pathways
Nucleus
Endoplasmic Reticulum
Lysosomes
Shared Pathways to Necrosis and Apoptosis
Programmed Necrosis
Ferroptosis
Pyroptosis
Necroptosis
Concluding Remark
Acknowledgments
References

Introduction
A common theme in disease is death of cells. In diseases ranging from stroke to
congestive heart disease to alcoholic cirrhosis of the liver, death of individual cells
leads to irreversible functional loss in whole organs and ultimately mortality. For
such diseases, prevention of cell death becomes a basic therapeutic goal. By contrast

27
in neoplasia, the purpose of chemotherapy is to kill proliferating cancer cells. For
either therapeutic goal, understanding the mechanisms of cell death becomes
paramount.

28
Modes of Cell Death
Although many stresses and stimuli cause cell death, the mode of cell death typically
follows one of two patterns. The first is necrosis, a pathological term referring to
areas of dead cells within a tissue or organ. Necrosis is typically the result of an
acute and usually profound metabolic disruption, such as ischemia (loss of blood
flow) and severe toxicant-induced damage. Since necrosis as observed in tissue
sections is an outcome rather than a process, the term oncosis has been introduced to
describe the process leading to necrotic cell death, but the term has yet to be widely
adopted in the experimental literature [1–3]. Here, the terms oncosis, oncotic
necrosis, and necrotic cell death will be used synonymously to refer both to the
outcome of cell death and the pathogenic events precipitating cell killing.
The second pattern is programmed cell death, most commonly manifested as
apoptosis, a term derived from an ancient Greek word for the falling of leaves in the
autumn. In apoptosis, specific stimuli initiate execution of well-defined pathways
leading to orderly resorption of individual cells with minimal leakage of cellular
components into the extracellular space and little inflammation [4–6]. Whereas
necrotic cell death occurs with abrupt onset after adenosine triphosphate (ATP)
depletion, apoptosis may take hours to go to completion and is an ATP-requiring
process without a clearly distinguished point of no return. Although apoptosis and
necrosis were initially considered separate and independent phenomena, an
alternate view is emerging that apoptosis and necrosis can share initiating factors
and signaling pathways to become extremes on a phenotypic continuum variously
called aponecrosis or necrapoptosis [7–9].

29
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